Evaluating the influence of marine protected areas on surf zone fish.

Marine protected areas (MPAs) globally serve conservation and fisheries management goals, generating positive effects in some marine ecosystems. Surf zones and sandy beaches, critical ecotones bridging land and sea, play a pivotal role in the life cycles of numerous fish species and serve as prime areas for subsistence and recreational fishing. Despite their significance, these areas remain understudied when evaluating the effects of MPAs. We compared surf zone fish assemblages inside and outside MPAs across 3 bioregions in California (USA). Using seines and baited remote underwater videos (BRUVs), we found differences in surf zone fish inside and outside MPAs in one region. Inside south region MPAs, we observed higher abundance (Tukey's honest significant difference [HSD] = 0.83, p = 0.0001) and richness (HSD = 0.22, p = 0.0001) in BRUVs and greater biomass (HSD = 0.32, p = 0.0002) in seine surveys compared with reference sites. Selected live-bearing, fished taxa were positively affected by MPAs. Elasmobranchs displayed greater abundance in BRUV surveys and higher biomass in seine surveys inside south region MPAs (HSD = 0.35, p = 0.0003 and HSD = 0.23, p = 0.008, respectively). Although we observed no overall MPA signal for Embiotocidae, abundances of juvenile and large adult barred surfperch (Amphistichus argenteus), the most abundant fished species, were higher inside MPAs (K-S test D = 0.19, p < 0.0001). Influence of habitat characteristics on MPA performance indicated surf zone width was positively associated with fish abundance and biomass but negatively associated with richness. The south region had the largest positive effect size on all MPA performance metrics. Our findings underscored the variability in species richness and composition across regions and survey methods that significantly affected differences observed inside and outside MPAs. A comprehensive assessment of MPA performance should consider specific taxa, their distribution, and the effects of habitat factors and geography.

Evaluación de la influencia de las áreas marinas protegidas sobre los peces de la zona de rompientes Resumen Las áreas marinas protegidas (AMP) cumplen los objetivos de conservación y manejo de pesquerías a nivel mundial, lo que genera efectos positivos en algunos ecosistemas marinos. Las zonas de rompientes y las playas arenosas, ecotonos importantes que conectan la tierra con el mar, tienen un papel esencial en el ciclo de vida de varios peces y fungen como áreas óptimas para la pesca recreativa y de sustento. A pesar de su importancia, estas áreas están poco estudiadas con respecto a la evaluación del efecto de las AMP. Comparamos la composición de peces del área de rompientes dentro y fuera de las AMP de tres bioregiones de California, EUA. Usamos chinchorros y videos submarinos con carnada (BRUVs) y descubrimos diferencias en los peces de la zona de rompientes dentro y fuera de las AMP en una región. Dentro de las AMP de la región sur observamos una mayor abundancia (diferencia significativa honesta de Tukey [DSH]  =  0.83, p = 0.0001) y riqueza (DSH  =  0.22, p = 0.0001) en los BRUV y una mayor biomasa (DSH  =  0.32, p = 0.0002) en los censos con chinchorro en comparación con los sitios de referencia. Los taxones seleccionados de peces de sustento fueron afectados de manera positiva por las AMP. Los elasmobranquios mostraron una mayor abundancia en los BRUV y una mayor biomasa en los censos con chinchorro dentro de las AMP de la región sur (DSH  =  0.35, p = 0.0003 y DSH  =  0.23, p = 0.008, respectivamente). Aunque no observamos una señal generalizada de las AMP para la familia Embiotocidae, la abundancia de Amphistichus argenteus juveniles y adultos, la especie pescada más abundante, fue mayor dentro de las AMP (prueba K­S D  =  0.19, p < 0.0001). La influencia de las características del hábitat sobre el desempeño de las AMP indicó que el ancho de la zona de rompientes está asociado de forma positiva con la abundancia y biomasa de los peces, pero de forma negativa con la riqueza. La región sur tuvo el mayor tamaño de efecto positivo sobre todas las medidas de desempeño de las AMP. Nuestros hallazgos destacan la variabilidad en la riqueza y composición de especies en todas las regiones y los censos que afectan significativamente las diferencias observadas dentro y fuera de las AMP. Una evaluación completa del desempeño de las AMP debe considerar taxones específicos, su distribución y el efecto de los factores de hábitat y la geografía.

Chronic Methamphetamine Self-Administration Dysregulates Oxytocin Plasma Levels and Oxytocin Receptor Fibre Density in the Nucleus Accumbens Core and Subthalamic Nucleus of the Rat.

The neuropeptide oxytocin attenuates reward and abuse for the psychostimulant methamphetamine (METH). Recent findings have implicated the nucleus accumbens (NAc) core and subthalamic nucleus (STh) in oxytocin modulation of acute METH reward and relapse to METH-seeking behaviour. Surprisingly, the oxytocin receptor (OTR) is only modestly involved in both regions in oxytocin attenuation of METH-primed reinstatement. Coupled with the limited investigation of the role of the OTR in psychostimulant-induced behaviours, we primarily investigated whether there are cellular changes to the OTR in the NAc core and STh, as well as changes to oxytocin plasma levels, after chronic METH i.v. self-administration (IVSA) and after extinction of drug-taking. An additional aim was to examine whether changes to central corticotrophin-releasing factor (CRF) and plasma corticosterone levels were also apparent because of the interaction of oxytocin with stress-regulatory mechanisms. Male Sprague-Dawley rats were trained to lever press for i.v. METH (0.1 mg/kg/infusion) under a fixed-ratio 1 schedule or received yoked saline infusions during 2-h sessions for 20 days. An additional cohort of rats underwent behavioural extinction for 15 days after METH IVSA. Subsequent to the last day of IVSA or extinction, blood plasma was collected for enzyme immunoassay, and immunofluorescence was conducted on NAc core and STh coronal sections. Rats that self-administered METH had higher oxytocin plasma levels, and decreased OTR-immunoreactive (-IR) fibres in the NAc core than yoked controls. In animals that self-administered METH and underwent extinction, oxytocin plasma levels remained elevated, OTR-IR fibre density increased in the STh, and a trend towards normalisation of OTR-IR fibre density was evident in the NAc core. CRF-IR fibre density in both brain regions and corticosterone plasma levels did not change across treatment groups. These findings demonstrate that oxytocin systems, both centrally within the NAc core and STh, as well as peripherally through plasma measures, are dysregulated after METH abuse.

Distribution and localisation of Gα proteins in the rostral ventrolateral medulla of normotensive and hypertensive rats: focus on catecholaminergic neurons.

About 860 G-protein-coupled receptors (GPCRs) mediate their actions via heterotrimeric G-proteins. Their activation releases Gα from Gßλ subunits. The type of Gα subunit dictates the major signalling proteins involved: adenylyl cyclase, PLC and rhoGEF. The rostral ventrolateral medulla (RVLM), containing the rostral C1 (rC1) cell group, sets and maintains the tonic and reflex control of blood pressure and a plethora of inputs converge onto these neurons. We determined the relative abundance of 10 Gα subunit mRNAs, representing the four major families, within the RVLM, using quantitative RT-PCR. In situ hybridisation (ISH) combined with immunohistochemistry (IHC) was used to quantify and compare this expression in rC1 with that in the A1 and A5 cell groups. The relative abundance of Gα subunit mRNAs and a comparison of gene expression levels were quantitatively determined in normotensive and hypertensive rat strains. All 10 Gα mRNAs were detected in the RVLM of Sprague-Dawley (SD) rats with relative abundance such that Gαs>Gαi2>Gαo>Gαq>GαL>Gα11>Gαi3>Gαi1>Gα12>Gα13. The high abundance of Gα mRNAs signalling via adenylyl cyclase indicates the importance of associated GPCRs. Within the rC1 and A1 groups similar differential Gα mRNA expression profiles were seen with Gαs being found in all rC1 cells, Gα11 absent and Gαi3 rarely expressed. Thus functionally distinct subgroups exist within the rC1 and A1 cell groups as differing distributions of Gα subunits must reflect the array of GPCRs that influence their activity. In contrast, all A5 cells expressed all Gα mRNAs suggesting a functionally homogeneous group. When the 10 Gα mRNAs of the RVLM in spontaneously hypertensive rats (SHR) were compared quantitatively to Wistar-Kyoto (WKY), only Gαs and Gα12 were significantly elevated. However when the expression in normotensive SD and WKY was compared with SHR no significant differences were evident. These findings demonstrate a range of GPCR signalling capabilities in brainstem neurons important for homeostasis and suggest a prominent role for signalling via adenylyl cyclase.

A randomized controlled trial of oral melatonin supplementation and breast cancer biomarkers.

We examined compliance with and the effects of melatonin supplementation on breast cancer biomarkers (estradiol, insulin-like growth factor I (IGF-1), insulin-like growth factor-binding protein 3 (IGFBP-3), and the IGF-1/IGFBP-3 ratio) in postmenopausal breast cancer survivors. In a double-blind, placebo-controlled study, postmenopausal women with a prior history of stages 0-III breast cancer who had completed active cancer treatment (including hormonal therapy) were randomly assigned to either 3 mg oral melatonin (n = 48) or placebo daily for 4 months. Plasma samples were collected at baseline and after the completion of the intervention. The primary endpoints were compliance and change in estradiol and IGF-1/IGFBP-3 levels. Ninety-five women were randomized (48 to melatonin and 47 to placebo). Eighty-six women (91%) completed the study and provided pre- and postintervention bloods. Melatonin was well tolerated without any grade 3/4 toxicity and compliance was high (89.5%). Overall, among postmenopausal women with a prior history of breast cancer, a 4-month course of 3 mg melatonin daily did not influence circulating estradiol, IGF-1, or IGFBP-3 levels. Compliance was comparable between the two groups. Short-term melatonin treatment did not influence the estradiol and IGF-1/IGBBP-3 levels. Effects of longer courses of melatonin among premenopausal women are unknown. Low baseline estradiol levels in our study population may have hindered the ability to detect any further estradiol-lowering effects of melatonin.

Isolation, identification and biological activity of gastrin-releasing peptide 1-46 (oGRP 1-46), the primary GRP gene-derived peptide product of the pregnant ovine endometrium.

We have previously demonstrated that pregnant ovine endometrium expresses the gastrin-releasing peptide (GRP) gene at a high level following conceptus implantation. Here we report the isolation, characterization and biological activity of ovine GRP 1-46, the primary product of this gene in the pregnant endometrium. Full thickness 125-140-day pregnant sheep uterus (term is 145 day) was homogenized in 80% acetonitrile/2% trifluoroacetic acid (1:7 ACN/TFA), concentrated on reverse-phase C18 cartridges and chromatographed successively on gel filtration (Sephadex G-50) and reverse-phase HPLC (C18 muBondapak). Purification was monitored by RIA. Purified GRP peptide was analysed by mass spectrometry giving a major mass ion at 4963 which corresponds exactly to GRP 1-46. Other mass ions from pro-GRP did not contain a biologically active N-terminus or antigenic determinant. Proteolytic cleavage of pro-GRP to give rise to GRP(1-46) would require preferential cleavage at the Glu-Glu bond by a Glu-C2-like enzyme, rather than the trypsin-like and C-terminal amidation enzymes (PAM) that produce GRP(18-27) and GRP(1-27) in other tissues. GRP 1-46 was synthesized and receptor binding and biological activity tested on a range of rodent and human cell lines that express GRP-related receptors GRPR, NMBR and BRS3. GRP 1-46 bound GRPR and NMBR with low affinity, and mobilized inositol phosphate in cell lines expressing the GRPR and NMBR, but not BRS-3. This study describes a new processed product of the GRP gene, GRP 1-46, which is highly expressed in the pregnant sheep endometrium and which acts as a weak agonist at the GRPR and NMBR.

Oestrogen receptor downregulation: an opportunity for extending the window of endocrine therapy in advanced breast cancer.

BACKGROUND: Advanced breast cancer is largely incurable and current treatment modalities are aimed towards restricting tumour growth, prolonging survival, palliating symptoms and maintaining quality of life (QoL). The development of breast cancer is strongly influenced by endogenous oestrogens (and other growth factors), leading to a strong focus on the development of antioestrogenic compounds for the treatment of hormone-sensitive advanced disease. DESIGN: This is a review of current endocrine therapies available for postmenopausal women with advanced breast cancer, examining the likely impact of newer agents on treatment strategies. RESULTS: In postmenopausal women, current treatment options include tamoxifen, aromatase inhibitors (AIs) and megestrol acetate. Fulvestrant ('Faslodex') is a new, well-tolerated, oestrogen receptor antagonist that has no known agonist effect and is at least as effective as the AI anastrozole for the treatment of postmenopausal patients with metastatic or advanced breast cancer who have progressed on prior endocrine therapy. Fulvestrant maintains QoL throughout successful treatment. CONCLUSIONS: Fulvestrant represents a new treatment option for postmenopausal women with advanced disease. New agents that appear to lack cross-resistance with existing treatments may be used to extend the time period during which endocrine therapy may be employed before the need for cytotoxic chemotherapy.

Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial.

PURPOSE: To compare the efficacy and tolerability of fulvestrant (formerly ICI 182,780) with anastrozole in the treatment of advanced breast cancer in patients whose disease progresses on prior endocrine treatment. PATIENTS AND METHODS: In this double-blind, double-dummy, parallel-group study, postmenopausal patients were randomized to receive either an intramuscular injection of fulvestrant 250 mg once monthly or a daily oral dose of anastrozole 1 mg. The primary end point was time to progression (TTP). Secondary end points included objective response (OR) rate, duration of response (DOR), and tolerability. RESULTS: Patients (n = 400) were followed for a median period of 16.8 months. Fulvestrant was as effective as anastrozole in terms of TTP (hazard ratio, 0.92; 95.14% confidence interval [CI], 0.74 to 1.14; P =.43); median TTP was 5.4 months with fulvestrant and 3.4 months with anastrozole. OR rates were 17.5% with both treatments. Clinical benefit rates (complete response + partial response + stable disease > or = 24 weeks) were 42.2% for fulvestrant and 36.1% for anastrozole (95% CI, -4.00% to 16.41%; P =.26). In responding patients, median DOR (from randomization to progression) was 19.0 months for fulvestrant and 10.8 months for anastrozole. Using all patients, DOR was significantly greater for fulvestrant compared with anastrozole; the ratio of average response durations was 1.35 (95% CI, 1.10 to 1.67; P < 0.01). Both treatments were well tolerated. CONCLUSION: Fulvestrant was at least as effective as anastrozole, with efficacy end points slightly favoring fulvestrant. Fulvestrant represents an additional treatment option for postmenopausal women with advanced breast cancer whose disease progresses on tamoxifen therapy.

The effect of residual mass size on response to chemotherapy after surgical cytoreduction for advanced ovarian cancer: long-term results.

We report an observational study of chemotherapeutic regression of ovarian tumor implants according to decrements in residual mass size after surgical cytoreduction. Cytoreductive operations were attempted on 74 consecutive patients with stages IIIB-IV disease referred for this purpose. Thirty-two patients had received one to four courses of preoperative chemotherapy (22 responses, no progressions). Postoperative chemotherapy followed current protocols at Dana Farber Cancer Institute (n=61) or referring institutions (n=13); 57 regimens contained cisplatin. Postchemotherapy response was assessed clinically or by second-look procedures. Negative findings were considered a complete remission. Masses > 1 cm were excised from 62 patients. Twelve patients were inoperable. Twenty-eight patients had complete remissions and the correlation between these and decrements in residual mass size was highly significant (P < 0.0001). Complete remissions had a uniform effect and were the only outcome predictive of survival. Preoperative treatment greatly facilitated cytoreduction but only masses 0-0.2 cm were sensitive to postoperative chemotherapy. Masses 0.5 cm or less were optimal. They made up 77% of operable patients and supplied 25 (89%) of the complete remissions. Cytoreduction is not always required but even large-volume disease in the upper abdomen can be safely excised. The concept that masses larger than 10 cm indicate general chemoresistance has not been sustained.

Nuclear factor 90 is a substrate and regulator of the eukaryotic initiation factor 2 kinase double-stranded RNA-activated protein kinase.

Nuclear factor 90 (NF90) is a member of an expanding family of double-stranded (ds) RNA-binding proteins thought to be involved in gene expression. Originally identified in complex with nuclear factor 45 (NF45) as a sequence-specific DNA-binding protein, NF90 contains two double stranded RNA-binding motifs (dsRBMs) and interacts with highly structured RNAs as well as the dsRNA-activated protein kinase, PKR. In this report, we characterize the biochemical interactions between these two dsRBM containing proteins. NF90 binds to PKR through two independent mechanisms: an RNA-independent interaction occurs between the N terminus of NF90 and the C-terminal region of PKR, and an RNA-dependent interaction is mediated by the dsRBMs of the two proteins. Co-immunoprecipitation analysis demonstrates that NF90, NF45, and PKR form a complex in both nuclear and cytosolic extracts, and both proteins serve as substrates for PKR in vitro. NF90 is phosphorylated by PKR in its RNA-binding domain, and this reaction is partially blocked by the NF90 N-terminal region. The C-terminal region also inhibits PKR function, probably through competitive binding to dsRNA. A model for NF90-PKR interactions is proposed.

Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer.

PURPOSE: To determine the response rate and toxicity profile of trastuzumab administered concurrently with weekly vinorelbine in women with HER2-overexpressing advanced breast cancer. PATIENTS AND METHODS: Forty women with HER2-positive (+3 by immunohistochemistry, n = 30; +2 or positive, n = 10) breast cancer were enrolled onto a study of trastuzumab (4 mg/kg x 1, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m2 weekly, with dose adjusted each week for neutrophil count). Eighty-two percent of women had received prior chemotherapy as part of adjuvant (30%), metastatic (25%), or both (28%) treatment, including substantial portions of patients who had previously received either anthracyclines (20%), taxanes (15%), or both types (38%) of chemotherapy. RESULTS: Responses were observed in 30 of 40 patients (overall response rate, 75%, conditional corrected 95% confidence interval, 57% to 89%). The response rate was 84% in patients treated with trastuzumab and vinorelbine as first-line therapy for metastatic disease, and 80% among HER2 +3 positive patients. High response rates were also seen in women treated with second- or third-line therapy, and among patients previously treated with anthracyclines and/or taxanes. Combination therapy was feasible; patients received concurrent trastuzumab and vinorelbine in 93% of treatment weeks. Neutropenia was the only grade 4 toxicity. No patients had symptomatic heart failure. Grade 2 cardiac toxicity was observed in three patients. Prior cumulative doxorubicin dose in excess of 240 mg/m2 and borderline pre-existing cardiac function were associated with grade 2 cardiac toxicity. CONCLUSION: Trastuzumab in combination with vinorelbine is highly active in women with HER2-overexpressing advanced breast cancer and is well tolerated.

The bovine papillomavirus E2 transactivator is stimulated by the E1 initiator through the E2 activation domain.

Bovine papillomavirus type 1 (BPV-1) encodes two regulatory proteins, E1 and E2, that are essential for viral replication and transcription. E1, an ATP-dependent helicase, binds to the viral ori and is essential for viral replication, while the viral transcriptional activator, E2, plays cis-dominant roles in both viral replication and transcription. At low reporter concentrations, E1 stimulates E2 enhancer function, while at high reporter concentrations, repression results. An analysis of cis requirements revealed that neither replication nor specific E1-binding sites are required for the initiators' effect on E2 transactivator function. Though no dependence on E1-binding sites was found, analysis of E1 DNA binding and ATPase mutants revealed that both domains are required for E1 modulation of E2. Through the use of E2 fusion-gene constructs we showed that a heterologous DNA-binding domain could be substituted for the E2 DNA-binding domain and this recombinant protein remained responsive to E1. Furthermore, E1 could rescue activation domain mutants of E2 defective for transactivation. These data suggest that E1 stimulation of E2 involves interactions between E1 and the E2 activation domain on DNA. We speculate that E1 may allosterically interact with the E2 activation domain, perhaps stabilizing a particular structure, which increases the enhancer function of E2.

Docetaxel administered on a weekly basis for metastatic breast cancer.

PURPOSE: To evaluate the safety and efficacy of weekly docetaxel in women with metastatic breast cancer. PATIENTS AND METHODS: Twenty-nine women were enrolled onto a study of weekly docetaxel given at 40 mg/m(2)/wk. Each cycle consisted of 6 weeks of therapy followed by a 2-week treatment break, repeated until disease progression or removal from study for toxicity or patient preference. Fifty-two percent of patients had been previously treated with adjuvant chemotherapy; 21% had received prior chemotherapy for metastatic breast cancer, and 31% had previously received anthracyclines. All patients were assessable for toxicity; two patients were not assessable for response but are included in an intent-to-treat analysis. RESULTS: Patients received a median of 18 infusions, with a median cumulative docetaxel dose of 720 mg/m(2). There were no complete responses. Twelve patients had partial responses (overall response rate, 41%; 95% confidence interval, 24% to 61%), all occurring within the first two cycles. Similar response rates were observed among subgroups of patients previously treated either with any prior chemotherapy or with anthracyclines. An additional 17% of patients had stable disease for at least 6 months. The regimen was generally well tolerated. There was no grade 4 toxicity. Only 28% of patients had any grade 3 toxicity, most commonly neutropenia and fatigue. Acute toxicity, including myelosuppression, was mild. Fatigue, fluid retention, and eye tearing/conjunctivitis became more common with repetitive dosing, although these side effects rarely exceeded grade 2. Dose reductions were made for eight of 29 patients, most often because of fatigue (n = 5). CONCLUSION: Weekly docetaxel is active in treating patients with metastatic breast cancer, with a side effect profile that differs from every-3-weeks therapy.

Phase I study of Doxil and vinorelbine in metastatic breast cancer.

BACKGROUND: Vinorelbine and Doxil (liposomal doxorubicin) are active chemotherapeutic agents in metastatic breast cancer. A phase I study was designed to evaluate combination therapy. PATIENTS AND METHODS: Thirty women with metastatic breast cancer were enrolled. Dose-limiting toxicity was determined through a dose escalation scheme, and defined for the first treatment cycle, only. Pharmacokinetic studies were performed during the first cycle of treatment. RESULTS: In the first cohort of Doxil 30 mg/m2 day 1 and vinorelbine 25 mg/m2 days 1 and 8, patients experienced severe neutropenia. Vinorelbine administration was changed thereafter to days 1 and 15 of each cycle. Dose limiting toxicity was observed at Doxil 50 mg/m2 and vinorelbine 25 mg/m2. Doxil 40 mg/m2 and vinorelbine 30 mg/m2 was defined as the maximally tolerated dose. Few toxicities (principally neutro penia) were seen at this dose level, with the notable absence of significant nausea, vomiting, or alopecia. Though 63% of patients had received prior anthracycline-based chemotherapy, only one patient developed grade 2 cardiac toxicity. Pharmacokinetic studies revealed prolonged exposure to high doxorubicin concentrations for several days following Doxil administration. CONCLUSIONS: Combination chemotherapy with Doxil and vinorelbine affords treatment with two active drugs in women with metastatic breast cancer, and appears to have a favorable toxicity profile. A schedule of Doxil 40 mg/m2 day 1 and vinorelbine 30 mg/m2 days 1 and 15 given every 28 days is recommended for phase II studies.

Sildenafil for women patients with antidepressant-induced sexual dysfunction.

In an open study, sildenafil (Viagra) was prescribed for nine women outpatients who reported sexual dysfunction induced by antidepressant medication, primarily selective serotonin reuptake inhibitors. A 50 mg dose of sildenafil was prescribed, and patients were instructed to take it approximately one hour before sexual activity. They were told to increase the dose to 100 mg on the next occasion if they experienced a partial response or a lack of response to sildenafil. The nine patients, all of whom had experienced either anorgasmia or delayed orgasm with or without associated disturbances, reported significant reversal of sexual dysfunction, usually with the first dose of 50 mg of sildenafil.

Static and fatigue biomechanical properties of anterior thoracolumbar instrumentation systems. A synthetic testing model.

STUDY DESIGN: A mechanical testing standard for anterior thoracolumbar instrumentation systems was introduced, using a synthetic model. Twelve recent instrumentation systems were tested in static and fatigue modes. OBJECTIVES: To establish the testing standard for anterior thoracolumbar instrumentation systems using a synthetic model and to evaluate the static and fatigue biomechanical properties of 12 anterior thoracolumbar instrumentation systems. SUMMARY OF BACKGROUND DATA: Although numerous studies have been performed to evaluate the biomechanics of anterior spinal instrumentation using a cadaveric or animal tissue, problems of specimen variation, lack of reproducibility, and inability to perform fatigue testing have been pointed out. In no studies has a precise synthetic testing standard for anterior thoracolumbar instrumentation systems been described. METHODS: An ultra-high-molecular-weight polyethylene cylinder was designed according to the anatomic dimensions of the vertebral body. Two cylinders spanned by spinal instrumentation simulated a total corpectomy defect, and a compressive lateral bending load was applied. The instrumentation assembly was precisely standardized. The static destructive and fatigue tests up to 2 million cycles at three load levels were conducted, followed by the failure mode analysis. Twelve anterior instrumentation systems, consisting of five plate and seven rod systems were compared in stiffness, bending strength, and cycles to failure. RESULTS: Static and fatigue test parameters both demonstrated highly significant differences between devices. The stiffness ranged from 280.5 kN/m in the Synthes plate (Synthes, Paoli, PA) to 67.9 kN/m in the Z-plate ATL (SofamorDanek, Memphis, TN). The Synthes plate and Kaneda SR titanium (AcroMed, Cleveland, OH) formed the highest subset in bending strength of 1516.1 N and 1209.9 N, respectively, whereas the Z-plate showed the lowest value of 407.3 N. There were no substantial differences between plate and rod devices. In fatigue, only three systems: Synthes plate, Kaneda SR titanium, and Olerud plate (Nord Opedic AB, Sweden) withstood 2 million cycles at 600 N. The failure mode analysis demonstrated plate or bolt fractures in plate systems and rod fractures in rod systems. CONCLUSIONS: The biomechanical testing standard for anterior thoracolumbar instrumentation systems was successfully designed. It provided a repeatable and consistent experimental condition and controlling dimensional and surgical factors. The comparison of 12 instrumentation systems highlights the importance of mechanically balanced device design without a weak link in the development of instrumentation.

Osteogenic protein versus autologous interbody arthrodesis in the sheep thoracic spine. A comparative endoscopic study using the Bagby and Kuslich interbody fusion device.

STUDY DESIGN: Using an in vivo interbody arthrodesis model, the efficacy of the Bagby and Kuslich (BAK) device packed with recombinant human osteogenic protein-1 (rhOP-1) was evaluated. OBJECTIVES: To compare the efficacy of osteogenic protein with that of autograft for interbody arthrodesis, with fusion success based on biomechanical, histologic, and radiographic analyses. SUMMARY OF BACKGROUND DATA: The use of recombinant human bone morphogenetic proteins (rhBMPs) as osteoinductive bone graft substitutes or expanders has recently gained considerable research interest, particularly when applied in posterolateral arthrodesis. However, whether these results can be extrapolated to a successful interbody spinal arthrodesis remains uncertain. METHODS: Twelve sheep underwent a multilevel thoracic spinal decompression by thoracoscopic approach. Three noncontiguous destabilization sites (T5-T6, T7-T8, T9-T10) were prepared and randomly treated as follows. Control group treatments were nonsurgical, destabilization alone, and empty BAK. Experimental groups were treated with autograft alone, BAK device packed with autograft, or BAK device packed with rhOP-1. Four months after surgery, interbody fusion status was quantified by biomechanical testing, computed tomography, microradiography, and histomorphometry. RESULTS: Results of biomechanical analysis showed statistically higher segmental stiffness levels when comparing the control and experimental groups with four of the five testing methods (P < 0.05). Computed tomography and microradiography characterized destabilization alone as producing one fusion in six preparations; the empty BAK, two in six;, autograft alone, four in eight; BAK with autograft, five in eight; and BAK with rhOP-1 group, six in eight-all evidenced by woven trabecular bone spanning the fusion sites. Histomorphometry yielded significantly more trabecular bone formation at the fusion sites in the three experimental groups than in the two control groups (P < 0.05). CONCLUSIONS: Interbody spinal fusions showing biomechanical and histomorphometric equivalency to autologous fusions have been achieved with rhOP-1. The functional unit stability and histologic osteointegration evidenced by the BAK/rhOP-1 complex shows this interbody arthrodesis technique to be a viable alternative toconventional autologous iliac crest, thereby obviating the need for an iliac crest donor site and associated patient morbidity.

Sildenafil for iatrogenic serotonergic antidepressant medication-induced sexual dysfunction in 4 patients.

OBJECTIVE: To evaluate the effect of sildenafil on iatrogenic serotonergic antidepressant-induced sexual dysfunction. METHOD: Four outpatients (2 men, 2 women) who developed sexual dysfunction (erectile impotence, anorgasmia) during treatment with a serotonin reuptake inhibitor antidepressant for psychiatric disorder were selected. Each subject was initially prescribed sildenafil 50 mg to be taken approximately 1 hour before sexual activity. The dose was increased to 100 mg for a partial or failed response. RESULTS: Four cases are detailed in case report fashion. All 4 had rapid reversal of their sexual dysfunction, usually with the first dose. Reversal equates to 1 successful use of sildenafil in each of 2 patients and 3 uses in 2 patients. CONCLUSION: Sildenafil may be an effective treatment for serotonergic antidepressant-induced sexual dysfunction and deserves further evaluation in randomized placebo-controlled studies.

Short-chain fatty acids inhibit intestinal trefoil factor gene expression in colon cancer cells.

Intestinal trefoil factor (ITF) gene expression was detected in five colon cancer cell lines. ITF was synthesized by mucous cells of LIM 1215 and LIM 1863 lines, from which it is secreted constitutively. The ITF mRNA transcript was estimated to be 0.6 kb. In LIM 1215 cells, the expression of ITF was potently and dose-dependently inhibited by short-chain fatty acids (butyrate > propionate > acetate) within 8 h of application. The inhibitory effect of butyrate was ablated by actinomycin D and preceded its effects on differentiation of LIM 1215 cells as indicated by induction of alkaline phosphatase activity and counting of periodic acid-Schiff-positive cells. The human ITF promoter contained an 11-residue consensus sequence with high homology to the butyrate response element of the cyclin D1 gene. Mobility shift assays show specific binding of this response element to nuclear protein extracts of LIM 1215 cells. We conclude that butyrate inhibits ITF expression in colon cancer cells and that this effect may be mediated transcriptionally and independently of its effects on differentiation.